Ibandronate polymorph

ABSTRACT

The present invention relates to a new polymorph crystal form of 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1 1-diphosphonic acid monosodium salt monohydrate (Ibandronate) with the following formula.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of European Application No.05100686.4, filed Feb. 1, 2005, which is hereby incorporated byreference in its entirety.

The present invention relates to a new polymorph crystal form of3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-diphosphonic acidmonosodium salt monohydrate (Ibandronate) with the following formula

and a process for its preparation.

Ibandronate is one of the most potent anti-resorptive drugs thatdirectly inhibit osteoclast activity and present an effectivepharmacologic alternative for controlling hypercalcemia. Ibandronatebinds to hydroxyapatite in calcified bone, rendering it resistant tohydrolytic dissolution by phosphatases, thereby inhibiting both normaland abnormal bone resorption. This drug increases bone mass anddecreases the risk of fractures and is therefore particularly welladapted to bone and calcium metabolic diseases such as for instanceosteoporosis or Paget's disease (EP-A 0252504)

It has been found that Ibandronate may exist in various polymorphs.

One polymorph of Ibandronate hereinafter also designated as polymorph Awas identified as being thermodynamically more stable, whereas a secondpolymorph of Ibandronate, hereinafter also designated as polymorph B, iseasier to separate within the production process.

The ability of a substance to exist in more than one crystal form isdefined as polymorphism and these different crystal forms are known as“polymorph modifications” or “polymorphs”. Polymorphism can influencemany aspects of solid state properties of a drug. Different crystalmodifications of a substance may differ considerably from one to anotherin different physical properties which may influence directly theirsolubility for instance. Polymorphism is found in several organiccompounds.

An exhaustive treatment of polymorphism in pharmaceutical and molecularcrystals is given e.g. by H. G. Brittain in Polymorphism inPharmaceutical Solids, H. G Brittain or, Marcel Dekker Inc., New York,1999 and in Solid-State Chemistry of Drugs, SSCI Inc., West Lafayette;Ind., 1999

Object of the present invention is to specifically isolate andcharacterize Ibandronate polymorph A and to develop a process for thepreparation of Ibandronate polymorph A.

The object has been achieved with the identification of crystallinepolymorph A of Ibandronate and with a process for its preparation asclaimed in the present invention.

Unless otherwise indicated, the following definitions are set forth todefine the meaning and scope of the various terms used and described inthe description.

The term “Ibandronate polymorph A” refers to the polymorph crystal formof 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-diphosphonic acidmonosodium salt monohydrate as defined in claims and description of thepresent invention.

The term “crystalline polymorph” refers to a crystal modification whichcan be characterized by analytical methods such as e.g. X-ray powderdiffraction, IR spectroscopy and Raman spectroscopy.

The term IR means infrared.

DESCRIPTION OF FIGURES

FIG. 1: shows an X-ray diffraction pattern of crystalline Ibandronatepolymorph A as obtained in example 1.

FIG. 2: shows an IR-spectrum of crystalline Ibandronate polymorph A

FIG. 3: shows a Raman spectrum of crystalline Ibandronate polymorph A

FIG. 4: shows an X-ray diffraction pattern of crystalline Ibandronatepolymorph B as obtained in Ref. example 2.

FIG. 5: shows an IR-spectrum of crystalline Ibandronate polymorph B

FIG. 6: shows a Raman spectrum of crystalline Ibandronate polymorph B.

The crystalline Ibandronate polymorph A of the present invention can becharacterized by an X-ray powder diffraction pattern havingcharacteristic peaks expressed in angle 2-theta at approximately:

Angle 2-theta Intensity [%] 10.2° 0.6 11.5° 0.7 15.7° 1.6 19.4° 1.926.3° 3.3

Angle 2-theta includes an uncertainty of ±0.2 (expressed in degrees),2-theta represent the reflection angle according to the Bragg law. Areflection at a glancing angle θ gives rise to a reflection at an angle2θ to the direction of the incident beam.

The crystalline Ibandronate polymorph A as described above can furtherbe characterized by the x-ray powder diffraction pattern as shown inFIG. 1.

The crystalline Ibandronate polymorph A can furthermore be characterizedby its IR absorption spectrum having characteristic peaks expressed incm⁻¹ at approximately:

Bands [cm⁻¹] 3678 3164 2854 1377 1288 1157 1094 1069 1035 966 951 933903 760 723

The term approximately means in this context that the cm⁻¹ value canvary by about ±4 cm⁻¹.

The crystalline Ibandronate polymorph A can further be characterized bythe IR absorption spectrum shown in FIG. 2.

The crystalline Ibandronate polymorph A as described above canfurthermore be described by Raman vibrational spectroscopy. The Ramanspectrum has the following characteristic bands expressed in cm⁻¹ atapproximately:

Bands [cm⁻¹] 2950 2927 2889 2851 1460 1443 1308 1137 1056 1024 954 904839 761 678

The term approximately means in this context that the cm⁻¹ value canvary by ±8 cm⁻¹.

The crystalline Ibandronate polymorph A can further be characterized bythe Raman spectrum shown in FIG. 3.

The crystalline Ibandronate polymorph A described above is furthercharacterized by a solubility in water of about 278 g/l at 25° C.

The process according to the present invention is characterized by acrystallization of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid monosodium salt or amonohydrate, a polymorph or a mixture of polymorphs at a temperature of50° C. to 70° C. in a polar solvent.

Water may be used as the polar solvent for crystallization.

Preferably the crystallization takes place in water at a temperature ofabout 60° C.

A polar aprotic solvent may be added for inducing the crystallization.

A suitable polar aprotic solvent is acetone.

Expediently the crystallization temperature is maintained for about 15minutes to about 120 minutes.

Starting product for the process of the present invention can either be3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-diphosphonic acidmonosodium salt e.g. obtained from a process as outlined in referenceexample 1, or crystalline Ibandronate polymorph B e.g. obtainedaccording to reference example 2, or from a mixture of crystallineIbandronate polymorph B with crystalline Ibandronate polymorph A.

The starting product can either be dissolved in the polar solvent atabout room temperature and then be warmed to the crystallizationtemperature or alternatively be dissolved at a higher temperature andthen be cooled to the crystallization temperature as indicated above.

Ethanol residues which may be present from the manufacturing process(according to reference example 1) can easily be removed by knownmethods e.g. by distilling the ethanol off as azeotrope.

Crystallization occurs spontaneously but can also be initiated byaddition of crystals of Ibandronate polymorph A.

The crystal suspension so obtained is generally cooled under stirringuntil crystallization is complete before the filtration takes place.

The whole crystallization process may be controlled regardingtemperature, heating and cooling periods with equipment common to theskilled practitioner.

Separation of the desired polymorph can be effected by common filtrationtechniques. As a rule the precipitate is washed with the polar solventused for the crystallization, preferably with a mixture of water andacetone in a ratio of about 1:1 (V/V).

Drying of the crystalline Ibandronate polymorph A preferably happens ata temperature from 40° C. to 80° C. for about 9 hours to 72 hours eitherat normal or at reduced pressure.

The crystalline Ibandronate polymorph according to the present inventioncan be obtained with a content of the crystalline Ibandronate polymorphA of at least 80%.

Alternatively the crystalline Ibandronate polymorph A can be obtained bytempering a moist3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acidmonosodium salt e.g. obtained from a process as outlined in referenceexample 1, or a crystalline Ibandronate polymorph B e.g. obtainedaccording to reference example 2, or from a mixture of crystallineIbandronate polymorph B with crystalline Ibandronate polymorph A at atemperature of 30° C. to 90° C.

Ethanol residues which may be present from the manufacturing process(according to reference example 1) can easily be removed by knownmethods e.g. by distilling the ethanol off as azeotrope.

The term “moist” in this context means that the starting productscontain some, as a rule about 10% water.

The crystalline Ibandronate polymorph A of the present invention can beused as a pharmaceutically active compound which acts as an efficientanti-resorptive drug that directly inhibits osteoclasts activity andthus also increases bone mass. Accordingly this polymorph can be usedfor the treatment and/or prevention of diseases which are associatedwith bone and calcium metabolic diseases such as for instanceosteoporosis or Paget's disease.

The invention therefore also relates to pharmaceutical compositionscomprising a crystalline Ibandronate polymorph A as defined above and apharmaceutically acceptable carrier and/or adjuvant.

The invention also encompasses a crystalline Ibandronate polymorph A asdescribed above for use as therapeutically active substances.

The following examples serve as illustration of the invention.

EXAMPLES X-Ray Powder Diffraction Measurement

The x-ray powder diffraction patterns of the individual crystallineIbandronate polymorphs A and B were recorded with a Bruker D8 AdvanceAXS diffractometry (geometry: Bragg-Brentano; radiation: CuKα in theangle range 2θ=2° to 40°; Cu secondary monochromator; step scan with0.02° and a measuring time of e.g. 4.0 s per step). The samples weighingapproximately 500 mg were prepared into carrier wells and exposed toCuKα radiation. Radiation diffracted at the lattice levels is convertedinto electronic signals by a scintillation counter and processed by thesoftware package “Diffrac plus”. The x-ray powder diffraction patternsof the individual crystalline Ibandronate polymorphs A and B are shownin FIGS. 1 and 4.

IR Measurement Method

The IR spectra of the individual crystalline Ibandronate polymorphs Aand B were recorded as film of Nujol suspension consisting of approx. 15mg of sample in approx. 15 mg of Nujol between two sodium chlorideplates. Measurements were carried out with an FT-IR spectrometer (IFS55(Bruker) or equivalent instrument) in transmittance mode (resolution 4cm⁻¹, detector: DTGS). The IR spectra of the individual crystallineIbandronate polymorphs A and B are shown in FIGS. 2 and 5.

Raman Measurement Method

The Raman spectra of the individual crystalline Ibandronate polymorphs Aand B were recorded as sample of about 20 mg of the powder and werefilled into a glass tube (shortened NMR tube). The samples were measuredwith the FT-Raman of Nicolet coupled to a Magna 860 (Nicolet) in 90°scattering arrangement, detector: InGaAs. Measurement parametersresolution 8 cm⁻¹; laser power 0.95 W, No of scan 300. The FT-Ramanspectra of the individual crystalline Ibandronate polymorphs A and B areshown in FIGS. 3 and 6.

Solubility Measurement

The solubility of the individual crystalline Ibandronate polymorphs Aand B was measured for various solutions. Approximately 10 g of thecorresponding polymorph A or B were suspended in three different buffersolutions at pH 2, pH 4 (Titrisol-buffer, citrate/HCl), at pH 7(methenamine buffer, HCl) or in water. The suspension was stirred for 24hours at 25° C. and was kept additionally 24 hours without stirring atthe same temperature. Solubility was calculated by titration accordingto the following method.

The residue was filtered, 2 ml of the filtrate taken, 5 ml of TitriplexIII solution were added and diluted with water to 100 ml. 2 ml of thissolution were added to approximately 0.1 ml of xylenol orange indicatorand the pH was adjusted to 6.5 by adding small portions of methenaminebuffer solution or 0.1 M hydrochloric acid. The solution is titratedimmediately with Th-DCTA-xylenol orange complex until the color changesfrom yellow to reddish-violet. The endpoint is determinedphotometrically.

Results are gathered in the following table

Polymorph A Polymorph B solubility in [g/l] solubility in [g/l]* pH 2280 274 pH 4 276 278 pH 7 292 299 water 278 279 *under at least partialconversion to polymorph A

Reference Example 1 Preparation of3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acidmonosodium salt

250 g (1.19 mol) N-methyl-N-pentyl-β-alanine hydrochloride, 233 g (2.84mol) phosphorous acid, 151 ml (1.65 mol) phosphorous oxychloride and 900ml diethyl carbonate were heated stepwise to 80° C. After 2 hoursreaction time under continued heating the mixture was cooled to 60° C.and 1733 ml demineralized water were added, followed by azeotropicdistillation of diethyl carbonate/water at 90 to 101° C. 358 mldemineralized water were added, the mixture was refluxed and water wasdistilled off. 316 ml demineralized water were added and water wasdistilled off twice. Finally 2040 ml demineralized water were added andthe residue was cooled to 24° C. The pH was adjusted at 23° C. withsodium hydroxide solution (50%) to 4.4. Thereafter, 1100 ml ethanol wereadded to start crystallization. The suspension was stirred for 8 hoursat 21 to 22° C. Then the solid was separated, washed with 344 ml coldethanol/demineralized water (7/5 V/V), subsequently with 344 mlacetone/demineralized water (5/2 V/V) and dried at 60° C. 315.6 g(73.7%) of the title product were obtained in the form of colorlesscrystals.

Assay (complexometric titration): 100.6% (calculated on the anhydrousand solvent free basis) Residual solvents: 2.3% ethanol (GC)

3.9% water (KF)

Reference Example 2 Preparation of Crystalline Ibandronate Polymorph B

55 g of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonicacid monosodium salt (obtained according to reference example 1) weredissolved in 240 ml demineralized water. 75 ml water were distilled off.After filtration, the remaining solution was brought to 35° C. and 190ml acetone were added in 20 minutes. Thereafter, the mixture was cooleduntil ≦25° C. under stirring, up to the complete crystallization. Theproduct was separated and washed with a mixture of acetone/demineralizedwater in a ratio of 1:1 (V/V). The product was dried in vacuum from 150to 20 mbar for 12 hours at 40° C. and 24 hours at 60° C.

Yield: 81%

Identified with x-ray powder diffraction as crystalline Ibandronatepolymorph B. (FIG. 4)

Example 1 Preparation of Crystalline Ibandronate Polymorph A

150 g of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonicacid monosodium salt (obtained according to reference example 1) weredissolved in 390 ml demineralized water at about 70-90° C. 205 ml waterwere distilled off. After filtration the solution was cooled to 60° C.and stirred for 45 minutes. Crystallization was initiated by means ofcrystalline Ibandronate polymorph A. After crystallization thesuspension was cooled to about 20-25° C. under stirring until thecrystallization was complete. The product was separated and washed witha mixture of 50 ml acetone/demineralized water in a ratio of 1:1 (V/V).The product was dried for 48 hours in a vacuum from 150 to 20 mbar at60° C.

Yield: 75%

Identified with x-ray powder diffraction as crystalline Ibandronatepolymorph A. (FIG. 1) Assay (complexometric titration): 101.0%(calculated on the anhydrous and solvent free basis)

Example 2 Preparation of Crystalline Ibandronate Polymorph A

150 g of crystalline Ibandronate polymorph B (obtained according toreference example 2) were dissolved in 185 ml demineralized water atabout 90° C. The solution was then cooled to 60° C. and stirred for 30min. Crystallization was initiated by means of crystalline Ibandronatepolymorph A. The suspension was cooled to about 20-25° C. until thecrystallization was complete. The product was separated and washed witha mixture of 50 ml acetone/demineralized water in a ratio of 1:1 (V/V).The product was dried for 48 hours in vacuum from 150 to 20 mbar at 60°C.

Yield: 80%

Identified with x-ray powder diffraction as crystalline Ibandronatepolymorph A. (FIG. 1)

Example 3 Preparation of Crystalline Ibandronate Polymorph A

150 g of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonicacid monosodium salt (obtained according to reference example 1), weredissolved in 390 ml demineralized water at about 70-90° C. 205 ml waterwere distilled off. After filtration the filtrate was cooled to 60° C.and stirred for 45 minutes. Crystallization was initiated by means ofcrystalline Ibandronate polymorph A. After crystallization a mixture ofdemineratized water/acetone (290 ml/518 ml) previously heated to 50° C.was added under stirring. Thereafter, the suspension was cooled to about20-25° C. under stirring, until the crystallization was complete. Theproduct was separated and washed with a mixture of 50 mlacetone/demineratized water in a ratio of 1:1 (V/V). The product wasdried for 48 hours in a vacuum from 150 to 20 mbar at 60° C.

Yield: 85%

Identified with x-ray powder diffraction as crystalline Ibandronatepolymorph A. (FIG. 1) Assay (complexometric titration): 101.0%(calculated on the anhydrous and solvent free basis)

Example 4 Preparation of Crystalline Ibandronate Polymorph A

100 g of crystalline Ibandronate polymorph B (obtained according toreference example 2) were dissolved in 304 ml demineralized water,warmed to 60° C. and it was filtrated. To the filtrate which was kept at55° C., 347 ml acetone were added dropwise during 1 hour. The mixturewas maintained at this temperature under stirring for 2 hours, thencooled to 15-20° C. The product was isolated by filtration and washedwith 120 ml of a solvent mixture of acetone/demineralized water 1:1(V/V). The product was dried in a vacuum from 150 to 20 mbar at 40° C.for 14 hours and then at 60° C. for 24 hours.

Yield: 88%

Identified with x-ray powder diffraction as crystalline Ibandronatepolymorph A. (FIG. 1)

Example 5 Preparation of Crystalline Ibandronate Polymorph A

100 g crystalline Ibandronate polymorph B (obtained according toreference example 2) were dissolved in 304 ml demineralized water,warmed to 60° C. and the solution was then filtrated. To the filtratewhich was kept at 55° C. 347 ml acetone were added dropwise during 1hour. In the course of the acetone addition crystals of Ibandronatepolymorph A were added in order to initiate crystallization. The mixturewas maintained at this temperature under stirring for 2 hours thencooled to 15-20° C. The product was isolated by filtration and washedwith 120 ml of a solvent mixture of acetone/demineratized water (1:1).The product was dried in a vacuum from 150 to 20 mbar at 40° C. for 14hours and then at 60° C. for 24 hours.

Yield: 90%

Identified with x-ray powder diffraction as crystalline Ibandronatepolymorph A. (FIG. 1)

Example 6 Preparation of Crystalline Ibandronate Polymorph A (Tempering)

30 g freshly precipitated Ibandronate obtained according to referenceexample 2, but directly used after filtration without drying andverified as polymorph B (moisture content about 10%, dried sampleverified as polymorph B) were heated for 45 min at 60° C. and 60 mbaruntil acetone is evaporated, followed by tempering at 60° C. and 900mbar for 19 hours and drying at 60° C. and 40 mbar for 9 hours underrotary motion.

Yield: quantitative

Identified with x-ray powder diffraction as crystalline Ibandronatepolymorph A. (content polymorph B: 19%)

Example 7 Preparation of Crystalline Ibandronate Polymorph A

30 g crystalline Ibandronate polymorph B obtained according to referenceexample 2 were suspended in a mixture of 95.4 ml demineralized water and103.4 ml acetone at 20° C. The suspension was heated to 60° C. in 1hour, stirred for 15 min., cooled to 20° C. in 1 hour and stirred for 5min. at 20° C. This cycle was repeated twice. The suspension was stirredfor 17 hours. The product was separated and dried for 18 hours in avacuum from 150 to 20 mbar at 60° C. Identification with x-ray-powderdiffraction as crystalline Ibandronate polymorph A (content polymorph B:23%).

1. A process for the preparation of a crystalline ibandronate polymorphform A having an X-ray powder diffraction pattern having characteristicpeaks expressed in angle 2-theta at approximately Angle 2-theta 10.2°11.5° 15.7° 19.4° 26.3°

comprising dissolving a member selected from the group consisting of3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-diphosphonic acidmonosodium salt, 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid monosodium saltmonohydrate, a polymorph form B of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid monosodium salt, and apolymorph mixture of form A and form B of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid monosodium salt thereof,and a polymorph mixture thereof in a polar solvent to form a solution;and adding a polar aprotic solvent to induce crystallization whilemaintaining the solution between 50° C. to 70° C.
 2. The processaccording to claim 1, wherein the polar solvent is water.
 3. The processaccording to claim 2, wherein the polar aprotic solvent is acetone. 4.The process according to claim 1 wherein the solution is maintainedbetween 50° C. to 70° C. for between 15 and 120 minutes after the polaraprotic solvent has been added.
 5. A process for the preparation of acrystalline ibandronate polymorph form A having an X-ray powderdiffraction pattern having characteristic peaks expressed in angle2-theta at approximately Angle 2-theta 10.2° 11.5° 15.7° 19.4° 26.3°

comprising tempering moist 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid monosodium salt,3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-diphosphonic acidmonosodium salt monohydrate, a polymorph form B of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid monosodium salt, and apolymorph mixture of form A and form B of 3-(N-methyl-N-pentyl)amino-1-hydroxypropane-1,1-diphosphonic acid monosodium salt thereof ata temperature of 30° C. to 90° C.